Monash Biomedicine Discovery Institute, Infection and Immunity Program and Department of Microbiology, Monash University, Melbourne 3800, Australia.
Fourth Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece.
J Infect. 2019 Oct;79(4):312-321. doi: 10.1016/j.jinf.2019.07.009. Epub 2019 Jul 30.
Polymyxins (i.e., polymyxin B and colistin) are used as a last-line therapy to combat multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance in K. pneumoniae is increasingly reported worldwide. This study identified the genetic variations responsible for high-level colistin resistance in MDR K. pneumoniae clinical isolates.
Sixteen MDR K. pneumoniae isolates were obtained from stool samples of 8 patients before and after colistin treatment. Their genomes were sequenced on Illumina MiSeq to determine genetic variations.
Fifteen of 16 isolates harboured ISKpn26-like element insertion at nucleotide position 75 of mgrB, abolishing its negative regulation on phoPQ; while colistin-susceptible ATH7 contained intact mgrB and phoQ. Interestingly, each of the 7 mgrB-disrupted, colistin-susceptible isolates contained a nonsynonymous substitution in PhoQ (G39S, L239P, N253T or V446G), potentially impairing its function and intergenically suppressing the effect caused by mgrB inactivation. Additionally, three of the 7 corresponding mgrB-disrupted, colistin-resistant isolates harboured a secondary nonsynonymous substitution in PhoQ (N253P, D438H or T439P).
This is the first report of phoQ mutations in mgrB-disrupted, colistin-susceptible K. pneumoniae clinical isolates. We also discovered multiple phoQ mutations in mgrB-disrupted, colistin-resistant strains. Our findings highlight the multifaceted molecular mechanisms of colistin resistance in K. pneumoniae.
多黏菌素（即黏菌素 B 和多黏菌素 E）被用作治疗多重耐药（MDR）肺炎克雷伯菌的最后手段。令人担忧的是，肺炎克雷伯菌对多黏菌素的耐药性在全球范围内日益增加。本研究鉴定了导致 MDR 肺炎克雷伯菌临床分离株高水平多黏菌素耐药的遗传变异。
从 8 名接受多黏菌素治疗前后的患者粪便样本中获得 16 株 MDR 肺炎克雷伯菌。对它们的基因组进行 Illumina MiSeq 测序，以确定遗传变异。
16 个分离株中的 15 个在 mgrB 的核苷酸位置 75 处携带 ISKpn26 样元件插入，从而破坏了其对 phoPQ 的负调控；而多黏菌素敏感的 ATH7 含有完整的 mgrB 和 phoQ。有趣的是，7 个 mgrB 缺失、多黏菌素敏感的分离株中的每一个都在 PhoQ 中发生了非同义突变（G39S、L239P、N253T 或 V446G），可能使其功能受损，并在基因间抑制 mgrB 失活引起的效应。此外，在这 7 个相应的 mgrB 缺失、多黏菌素耐药的分离株中，有 3 个在 PhoQ 中发生了次要的非同义突变（N253P、D438H 或 T439P）。
这是首次报道 mgrB 缺失、多黏菌素敏感的肺炎克雷伯菌临床分离株中存在 phoQ 突变。我们还发现了 mgrB 缺失、多黏菌素耐药株中存在多种 phoQ 突变。我们的研究结果强调了肺炎克雷伯菌对多黏菌素耐药的多种分子机制。
